Type 2 diabetes (T2D) is a major cause of morbidity and mortality, affecting >400 million people worldwide and >30 million in the US alone; >25% of Americans aged ?60 years suffer from T2D. Similar rates of T2D have been observed in Finland. T2D incidence and prevalence are increasing rapidly. In the US, health-care costs of diabetes in 2012 were estimated at $176 billion, >15% of total US health-care costs. The goals of the Finland- United States Investigation of NIDDM Genetics (FUSION) study are to identify genetic variants, target genes, and genetic mechanisms that influence T2D risk and variability in T2D-related quantitative traits (QTs), and to foster clinical translation of these findings. Improved understanding of the genetic and epigenomic bases of T2D and related QTs has the potential to reduce the impact of the T2D epidemic by supporting identification of novel therapies, enabling better targeting of therapies, providing more accurate T2D risk prediction, and advising lifestyle changes in at-risk individuals. In this competing renewal, we propose to (1) discover and fine map genetic loci that influence T2D risk and QT variability using array- and sequence-based GWAS in our own expanded set of samples and through meta-analysis of Finnish, European, and multi-ancestry samples; (2) select individuals with and without high-interest low-frequency T2D- and QT-associated variants for genotype-based callback and targeted phenotyping to test for association and identify physiological mechanisms; (3) carry out deep, linked- read (10x Genomics) whole genome sequencing for 331 FUSION tissue donors to capture the full spectrum of genetic variation and haplotypes; (4) carry out integrated analysis of linked-read DNA sequence with diverse molecular profiles (RNA transcript, open and active chromatin, metabolomics, DNA methylation) and T2D and QTs in our tissue donors, to understand the biology underlying T2D- and QT-associated variants and genes in skeletal muscle, subcutaneous adipose, induced pluripotent stem cell (iPSC)-derived pancreatic beta-cells; (5) integrate genomic assay results across multiple tissues, including also liver and visceral adipose, to understand the contributions of tissues, genes, variants, and biological mechanisms to T2D risk and QT variability; and (6) accelerate advances in T2D genetics through enhanced data sharing and support for easy exploration and visualization of our study results by any investigator. Successful completion of these aims will improve understanding of T2D etiology and point the way to novel methods of prevention and treatment. The longstanding, productive collaboration of our FUSION study team makes achievement of these aims feasible and likely to be highly informative to the public health crisis posed by T2D. Methods developed and lessons learned here will be useful in the study of other genetic diseases and traits.